Most patients prefer to take orally administered medicaments over other routes of administration. However, in order to be acceptable to patients, an oral drug product must be easily swallowed and without unpleasant or bitter taste or other undesirable organoleptic properties.
N-acetylcysteine, or N-acetyl-L-cysteine, often also abbreviated as NAC, is a mucolytic agent used in many countries in the management of symptoms associated with cough and the common cold. Other uses include the treatment of paracetamol overdose and sulphate depletion. The compound has a highly unpleasant taste and develops a smell of sulphur, especially over time through trace degradation.
As a mucolytic agent, N-acetylcysteine is typically administered at a dose of 200 mg three times a day, or more commonly 600 mg once a day. Because such dose can only be accommodated in relatively large dosage units which may not be easy to swallow, the compound is often formulated as an effervescent tablet or effervescent granules which are much easier to take than a conventional tablet or capsule containing such high dose.
While taste masking is generally rather easy to achieve with a conventional tablet which may be coated with a suitable polymeric coating, and also in the case of a capsule formulation wherein the capsule shell itself provides a barrier which prevents contact between the active ingredient and the oral mucosa of the patient during administration, it is more challenging to mask the taste of a compound like N-acetylcysteine when formulated as a dispersible, effervescent, or orally disintegrating dosage form or as granules for direct oral administration (“direct-to-mouth granules”), because in these cases the dosage unit is not swallowed as a whole, but the formulation comes into substantial contact with the oral mucosa. In the case of effervescent formulations, the drug typically dissolves in a larger amount of water, such as 200 mL, and in this diluted form, sufficient taste masking may be achieved through the incorporation of sweetening agents and flavours. Most challenging in terms of taste is the formulation of the active ingredient in dosage forms whose administration potentially allows the drug to contact the oral mucosa in concentrated form, as in the case of orally disintegrating tablets or granules for direct oral administration. On the other hand, such dosage form designs are highly desirable for high-dose drugs because of their excellent swallowability even without water.
Some compositions comprising N-acetylcysteine and taste-masking components are known. For example, EP-A 0 839 528 discloses N-acetylcysteine tablet or granulate compositions formulated with cyclodextrins, which are complexing agents with cavities capable of hosting small molecules. In addition, the formulations comprise sweetening agents such as sorbitol and aspartame, and various flavours. However, cyclodextrins are expensive excipients, and for effective taste-masking require incorporation in relatively large amounts. Also the use of sweeteners and flavouring agents to divert the patient from an active ingredient's unpleasant sensory attributes often requires the use of large amounts of these excipients to achieve a good taste-masking effect. According to EP-A 0 839 528, the active ingredient is incorporated into the formulations only at a level of 5 to 10 wt.-%.
A generally more effective taste-masking approach is to provide a coating on the surface of the active ingredient. The coating serves as a physical barrier layer between the active ingredient and the patient's taste buds and olfactory receptors.
In addition, a coating may be useful also to protect a sensitive or labile active ingredient during storage.
In principle, taste-masking coating may be polymeric film coatings or lipidic coatings. Polymeric coating systems are sprayed onto drug cores as aqueous or organic solutions or dispersions. A disadvantage of organic solvents is their need for special equipment and their negative impact on the environment. Aqueous coating systems also consume substantial energy, as the polymeric coating material must be heated above its film-forming temperature in order to coalesce, and the removal of water require more extensive drying than that of typical organic solvents. Moreover, many polymeric coating systems show curing effects, i.e. their properties change over time, so that the drug dissolution behaviour may become compromised during storage.
Lipidic coating systems, such as coatings based on waxes like carnauba wax, do not require a solvent to be applied to drug-containing cores: They may often be used as melts in hot-melt coating processes. On the other hand, these types of coatings, due to the poor water solubility of its main constituents, also tend to have substantial negative impact on the drug's release profile, especially if rapid drug release is required. In such cases, wax coatings are often not successful.
Moreover, the stability of a lipidic or waxy taste-masking coating itself over time can also impact the release profile of the active ingredient. The conversion of an initially formed polymorph of a coating excipient to a thermodynamically more stable crystal form over time during the course of storage, sometimes also triggered by an exposure to different environmental conditions, can lead to significant and undesirable variations in the drug dissolution profile of the composition.
Furthermore, also the hot-melt processing conditions may be critical to temperature-sensitive drug compounds like N-acetylcysteine. Depending on the type of lipidic or waxy coating material, the coating process are sometimes conducted at temperatures of higher than 60° C., and sometimes also higher than 80° C. or even 100° C.
For these reasons, no suitable method for providing N-acetylcysteine with a taste-masking coating has been developed so far, even though there is a clear need for such coated N-acetylcysteine.
WO 2008/071407 A2 discloses immediate or rapid release pellets comprising cefpodoxim, an antibiotic compound having a poor taste. The pellets exhibit a taste-masking coating comprising carnauba wax and a hydrogel former such as a cellulose polymer derivative, alginate or gum. It is mentioned in the document that many lipophilic substances, such as cocoa butter or Precirol, are prone to polymorphic changes during storage. As the structural changes would lead to inconsistencies in the dissolution profiles, such compounds are deemed to be unsuitable for use as coating excipients for these pellets. The document therefore teaches the use of waxes such as carnauba wax which have a high melting range and which do not exhibit any polymorphic changes.
U.S. Pat. No. 5,891,476 discloses acetaminophen particles or granules coated with a non-polymorphic waxy component such as carnauba wax and optionally other lipid components and/or surfactants. According to the document, the use of such waxes removes the risk of variable dissolution rates resulting from changing morphology of the coating over time and under different conditions.
However, a disadvantage in using waxy components having a high melting point such as carnauba wax (melting range approx. 82 to 86° C.) in hot-melt coatings is that the active ingredient itself may also be subjected to the higher temperatures required to maintain the coating components in melt-phase during the coating process. Higher temperatures during processing can increase the degradation of thermo-labile active ingredients. Moreover, hot-melt coating processes involving molten carnauba wax are very difficult to handle because the coating composition must be kept at even higher temperatures, e.g. at about 100° C. or higher, and since this wax solidifies very rapidly upon cooling down, it tends to clog the tubes through which it is pumped to the spray nozzle, as well as the nozzle itself.
WO 2010/070028 A1 discloses various taste-masked, hot-melt coated compositions incorporating the active ingredients acetaminophen, ranitidine, and caffeine. The coatings comprise, as a meltable lipophilic excipient, stearic acid, Precirol ATO 5 (a mixture of mono-, di- and triglycerides of palmitic and stearic acid), or Compritol 888 ATO (glyceryl behenate). The coatings further comprise a release compound, i.e. a compound which enhances the disintegration of the taste-masking layer in the gastrointestinal fluid, such as by the formation of pores or holes through swelling (e.g. Amberlite IRP 88) or carbon dioxide release (e.g. calcium carbonate); and a surfactant or other substance (e.g. PEG 3000 or Tween 20) which is incorporated to achieve a homogeneous distribution of the release compound in the meltable lipophilic excipient. However, the resulting coating compositions are rather complex. Due to the insolubility of the release compound in the meltable lipophilic compound, there is a risk of phase separation during the coating process, leading to poor reproducibility. Moreover, as the document is silent on this aspect, it is unclear whether the release profiles achieved with such complex and inherently incompatible coating compositions are stable under storage conditions.
US 2010/0092569 A1 relates to the taste-masking of conjugated linoleic acid compounds by suspending an adsorbate of the active ingredient on silica powder in a molten lipid matrix and subsequent spray cooling, such as to form coated particles. The lipid matrix comprises triglycerides of C16, C18, C20 and C22 saturated fatty acids and 3 wt.-% of an unidentified emulsifier whose function is to ensure a homogeneous dispersion of the active ingredient in the molten lipid. The purpose of the coating is to protect the light- and air-sensitive linoleic acid compound from degradation. The taste-masked product is used as an additive in animal feed.
However, the preparation of a melt suspension involves the full exposure of the active ingredient to temperatures higher than the melting range of the lipid, in the present case about 70° C., which may be acceptable in the case of some active ingredients or in the case of animal feeds, but not for temperature-sensitive pharmaceutical compounds for human use. Moreover, the document is silent as to the resulting dissolution profiles, which do not appear to have any relevance in this case.
It is an object of the invention to provide an improved method for the taste-masking of N-acetylcysteine. Moreover, it is an object to provide an improved taste-masked form of N-acetylcysteine which exhibits rapid drug dissolution and a stable dissolution profile. A further object is to provide improved pharmaceutical compositions comprising taste-masked N-acetylcysteine with rapid drug dissolution. A yet further object is to provide taste-masked compositions which may be manufactured at moderate temperatures in order to avoid the degradation of sensitive compounds such as N-acetylcysteine, as well as processes by which taste-masked compositions of sensitive compounds may be prepared. Moreover, it is an object to overcome one or more of the limitations or disadvantages associated with the prior art. Other objects will become clear on the basis of the description and the claims.
These and other objects are achieved by the subject-matter as defined in the independent claims below, with particular embodiments outlined in the dependent claims.